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The Temporal Mutational and Immune Tumour Microenvironment www.nature.com/npjbcancer ARTICLE OPEN The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers ✉ Leticia De Mattos-Arruda 1,2,3 , Javier Cortes 4,5,6,7,8, Juan Blanco-Heredia1,2, Daniel G. Tiezzi 3,9, Guillermo Villacampa10, Samuel Gonçalves-Ribeiro 10, Laia Paré11,12,13, Carla Anjos Souza1,2, Vanesa Ortega7, Stephen-John Sammut3,14, Pol Cusco10, Roberta Fasani10, Suet-Feung Chin 3, Jose Perez-Garcia4,5,6, Rodrigo Dienstmann10, Paolo Nuciforo10, Patricia Villagrasa12, Isabel T. Rubio10, Aleix Prat 11,12,13 and Carlos Caldas 3,14 The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of- opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN- NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of 1234567890():,; subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment. npj Breast Cancer (2021) 7:73 ; https://doi.org/10.1038/s41523-021-00282-0 INTRODUCTION transcriptomic changes across breast cancer patients receiving 13 Breast cancer is the most commonly diagnosed cancer and the neoadjuvant therapy . Therefore, the neoadjuvant setting in breast leading cause of female cancer death worldwide1. It represents a cancer provides a window-of-opportunity to explore the genomic and heterogeneous group of tumours with characteristic molecular microenvironment modulation of tumours exposed to therapy over 5,14 features, prognosis and responses to available therapy2,3. time . In the early stage breast cancer setting, treatment decisions are In this study, we temporally characterised the mutational, gene guided by clinical subtypes, namely hormone receptor (HR) positive expression, pathway enrichment and tumour-infiltrating lymphocytes (HR+/HER2−), human epidermal growth factor receptor 2 amplified (TILs) dynamics across different timepoints over a 12-week period in (HER2+) and triple-negative breast cancer (TNBC). This general HER2-negative primary breast cancers enrolled in the single-arm classification does not take into account the complex genomic SOLTI-1007 NEOERIBULIN phase II clinical trial (NCT01669252). We landscape and breast cancer evolution during therapy administration show that the mutational and immune tumour microenvironment and disease recurrence or progression4,5. remodelling of HER2-negative primary breast cancers provides a path Currently, the biology of the neoadjuvant response to therapy is forward for gathering biological insights from primary breast cancers. underrepresented in the literature. Large-scale genomic studies have mostly focused on the analysis of single primary breast cancers2,3,6–9, which do not provide information on cancers over time. The analysis RESULTS ofthegeneexpressionlandscape of tumours has been shown to A clinical cohort of HER2-negative breast cancer patients correlate with response to cytotoxic therapies10–12,thoughvery Primary breast cancer tumour specimens were obtained from the limited work has been done to characterise the genomic and open-label, single-arm SOLTI-1007 NEOERIBULIN phase II clinical 1IrsiCaixa, Germans Trias i Pujol University Hospital, Badalona, Spain. 2Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain. 3Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK. 4Oncology Department International Breast Cancer Center (IBCC), Quiron Group, Barcelona, Spain. 5Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. 6Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. 7Breast Cancer Research program, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain. 8Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain. 9Breast Disease Division, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil. 10Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain. 11Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. 12SOLTI Breast Cancer Research Group, Barcelona, Spain. 13Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain. 14Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. ✉ email: [email protected] Published in partnership with the Breast Cancer Research Foundation L. De Mattos-Arruda et al. 2 a Whole exome seq NanoString gene Tumor infiltrating 88 samples, 35 patients expression profiling lymphocytes (TILs) 96 samples, 35 patients 105 samples, 35 patients Excluded: Excluded: Purity < 20%,reads < 15 PAM50 PAM50 not available Excluded: Low sequencing quality subtyping 1 sample Not evaluated or not available 65 primary tumors and one 547 genes 91 primary tumors metastasis across 28 patients 96 primary tumors across 34 patients across 35 patients ORR at Surgery (good responders vs poor responders) - TMB, clonality - neoantigen prediction - gene expression -TILs counts b Stage I/II Eribulin 1.4mg/m2 Day 1 and 8, every 21 days HER2- breast cancer Cycle 1 Cycle 2 Cycle 3 Cycle 4 Surgery Adjuvant therapy as per investigator choice (anthracycline recommended) .... recurrence 1234567890():,; Core or Core Biopsy (V2) (V3) (VR) incisional biopsy (V1) Physical exam ORR Imaging diagnosis Mamogram/ US pCRb V1V2V3 VR Total WES 28 24 13 1 66 Gene Expresion 35 3129 - 96 TILs 34 29 28 - 91 Her2Enriched (2.9%) PR (40%) Luminal B CR (14.3%) (22.8%) Basal-like (34.3%) PD (11.4%) NA (2.9%) SD (34.3%) Luminal A (37.1%) PAM50 (V1) ORR surgery (V3) Fig. 1 The study schematics. a. Tumour tissue samples underwent (i) Whole-exome sequencing (WES) for mutation and clonality detection followed by neoantigen prediction; (ii) Nanostring gene expression profiling; and (iii) stromal TILs counting. Our goal was to select samples that passed quality control and perform the temporal characterisation of the mutational, gene expression and TILs in serial primary HER2- negative breast cancers that were good responders or poor responders to eribulin. DNA sequencing (WES) was performed in 88 primary invasive breast cancers and matched the normal DNA of each patient. Of these, 66 tumour samples were used for mutational and clonality analyses. RNA-Nanostring gene expression profiling was performed in 96 primary invasive breast cancers. From the DNA sequencing data, candidate neoantigens were predicted. Stromal TILs were counted from the H&E slides in 91 out of 105 tumour specimens. Clinical features and the PAM50 intrinsic molecular subtypes of each of the sequential primary tumour’s biopsies were examined. TMB tumour mutation burden, ORR overall response rate. b Schematics of the clinical trial. Temporal tumour sampling and a number of samples included in each analysis and time point are depicted. Distribution of PAM50 molecular intrinsic breast cancer subtypes at V1 (diagnostic biopsy), and ORR at V3 (surgery). E eribulin administration, V1 visit one, V2 visit two, V3 visit three, VR visit recurrence, CR complete response, PR partial response, SD stable disease, PD progressive disease. trial (NCT01669252). We included sequential primary tumour adjuvant therapy. Although six patients presented clinic-radiologic biopsies from 35 HER2-negative (22 HR-positive and 13 HR- recurrence, tumour material was available at the time of negative) breast cancer patients (1–3 tumour tissue samples per recurrence in one patient. The samples that passed quality control patient) during eribulin administration. Whole-exome data (N = (i.e., tumour cellularity, sequencing quality, see Fig. 1a and 88 samples) generated mutational profiles and candidate neoanti- “Methods”), were further processed and analysed. gens and were analysed along with RNA-Nanostring 545-gene Clinical features of the cohort are summarised in Table 1 and expression (N = 96 samples) and stromal TILs (N = 105 samples) the schematics of the study design are shown in Fig. 1b. The 5- from 35 patients
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